Elsevier

Molecular Immunology

Volume 73, May 2016, Pages 46-52
Molecular Immunology

Anti-inflammatory TIPE2 inhibits angiogenic VEGF in retinal pigment epithelium

https://doi.org/10.1016/j.molimm.2016.03.013Get rights and content

Highlights

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    TIPE2 is involved in the maintenance of RPE cell viability.

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    TIPE2 is down-regulated in inflammatory RPE cells and animal CNV models.

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    TIPE2 inhibits TNF-α and IL-1β in RPE cells.

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    TIPE2 inhibits VEGF in RPE cells.

Abstract

Choroidal neovascularization (CNV) is a pathological feature which commonly occurs in ocular diseases. This condition is characterised by vasculogenesis and angiogenesis underlying the neuroretina, with retinal pigment epithelium (RPE) and choroid as main targets. Inflammation and immunity are crucial in the early development of CNV. Tumour necrosis factor (TNF) α-induced protein-8 like-2 (TIPE2 or TNFAIP8L2), a recently identified gene, is a negative regulator of innate and adaptive immunity which participates in inflammatory homeostasis. We determined the expression of TIPE2 in normal and inflamed RPE cells, and evaluated the relationship of TIPE2 with factors associated with inflammation and angiogenesis. TIPE2 is present in both the cytoplasm and nucleus of human RPE cells and is down-regulated in the inflammatory state with decreased cell viability. Knock-down of TIPE2 by a specific short interfering RNA increases the expression levels of TNF-α, IL-1β and angiogenic vascular endothelial growth factor (VEGF), particularly under the stimulation of lipopolysaccharide. In consideration of the vital role of VEGF in the final stage of neovascularization, the anti-inflammatory TIPE2 is also anti-angiogenic and may participate in CNV formation.

Introduction

Choroidal neovascularization (CNV) is a pathological feature which commonly occurs in several ocular diseases, including age-related macular degeneration (AMD), high myopia and idiopathic CNV. Vasculogenesis and angiogenesis underlying the neuroretina are the final features of CNV. The presence of CNV indicates poor visual prognosis. Retinal pigment epithelium (RPE) plays a vital role in the pathology of CNV (Bhutto and Lutty, 2012, Grossniklaus et al., 2002). Current treatment of CNV is targeted to the formed neovascularization and could only partially prevent vision deterioration. Recent studies have suggested the significance of inflammation and immunity in the early development of CNV (Grossniklaus et al., 2002, Penfold et al., 2001). Managing CNV before vasculogenesis and angiogenesis is more vision protective.

Tumour necrosis factor (TNF)-α-induced protein-8 like-2 (TIPE2 or TNFAIP8L2) is a recently identified gene. As a new member of the TNF-α-induced protein 8 family, TIPE2 negatively regulates innate and adaptive immunity, and plays an important role in inflammatory homeostasis (Sun et al., 2008). TIPE2 deficiency in mice leads to multiple organ inflammation, and TIPE2 down-regulation in humans is associated with systemic autoimmunity (Li et al., 2009, Sun et al., 2008). In addition, TIPE2 is a biomarker and inhibitor of tumour progression.

In the present study, we examine the expression of TIPE2 in normal and inflamed RPE cells to evaluate the relationship of TIPE2 with factors affecting inflammation and angiogenesis. We may also consider the novel anti-inflammatory TIPE2 as anti-angiogenic.

Section snippets

Pre-test

Animal experiments were performed in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals by the National Academy of Sciences published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996). The protocol was reviewed and approved by the Institutional Animal Care and Use Committee of Qilu Hospital, Shandong University.

An animal model of CNV was induced

Decreased expression of TIPE2 in experimental CNV in the pre-test

The mRNA expression of TIPE2 in the pigmented layer of the CNV samples 3 days after photocoagulation significantly decreased compared with that of the normal mice (one set for the control vs. 0.58 ± 0.05 for the CNV samples 3 days after induction, n = 3, p <0.01). The mRNA expression of TIPE2 was almost depleted at 7 days (0.94 ± 0.02 vs. 0.06 ± 0.05 at 3 d, n = 3, p < 0.001) (Fig. 1b). Same decreased protein expression of TIPE2 in the CNV samples was found in the Western blot analysis (one set for the

Discussion

CNV is a pathohistological feature which commonly occurs in several diseases, such as AMD, pathological myopia and idiopathic CNV; RPE layer and choroidal tissue are the primary pathological sites (Hageman et al., 2001, Nagineni et al., 2012, Young, 1987). During CNV formation, RPE, choroid microvascular endothelial cells and other inflammatory cells act in different stages (Grossniklaus and Green, 2004). Although vasculogenesis and angiogenesis of the choroid are the final characterisation of

Conclusion

TIPE2 exhibits an anti-inflammatory function in cultured human RPE cells; TIPE2 also exerts an anti-VEGF effect. Further studies need to be conducted to elucidate the precise function and mechanisms of TIPE2 in CNV development.

Limitation

The main limitation is that we did not test the effects of over expression of TIPE2 in RPE cells, which may provide more proof.

Funding

This project was sponsored in part by the Natural Science Foundation of Shandong Province (Grant No. ZR2012HM024) and Independent Innovation Foundation to Universities and Colleges by Jinan Science and Technology Bureau (Grant No. 201202036). The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflict of interest

The authors declare that they have no competing interests.

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